This document summarizes the results of two randomized, double-blind, placebo-controlled clinical trials that evaluated the efficacy and safety of fixed doses of 50 mg and 100 mg of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine succinate for the treatment of major depressive disorder. The trials found that both the 50 mg and 100 mg doses were more effective than placebo at reducing depression symptoms, based on evaluations of depression rating scales. The most common adverse events reported with desvenlafaxine treatment were dry mouth, nausea, dizziness, insomnia, and constipation. Discontinuation rates due to adverse events were higher with desvenlafaxine than placebo.

1. Evaluation of the Efficacy and Safety of Fixed Doses of Desvenlafaxine Succinate at 50 mg and 100 mg
in Outpatients With Major Depressive Disorder in 2 Placebo-Controlled Trials
Michael Liebowitz, MD1; Stuart Montgomery, MD, PhD2; Patrice Boyer, MD, PhD3; Amy L. Manley4; Sudharshan K. Padmanabhan4; Raj Tummala, MD4; Jean-Michel Germain, PhD5; Claudine Brisard, MD5; Karen A. Tourian, MD4
1
Columbia University, New York, New York; 2Imperial College School of Medicine, London, England; 3University of Ottawa, Ontario, Canada; 4Wyeth Research, Collegeville, Pennsylvania; 5Wyeth Research, Paris, France
Abstract Results Other Secondary Efficacy Measures
Table 3. Primary Efficacy End Points: HAM-D17, Adjusted Mean Change From
Table 4. Secondary Efficacy End Points, LOCF Analysis: Final On-Therapy Evaluation
Baseline, ITT Population, LOCF, Observed Case, and MMRM Analyses
Objective: To assess the efficacy of the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine Patients
US Study International Study
US Study International Study
succinate (desvenlafaxine) at 50 mg/d and 100 mg/d doses for the treatment of major depressive disorder (MDD).
Difference Difference
Table 1. Patient Disposition
Methods: Two identically designed multicenter, randomized, double-blind, placebo-controlled studies were Difference in Difference in in Adjusted in Adjusted
Adjusted Adjusted Adjusted Adjusted
conducted: 1 in the United States (US) and 1 in Europe and South Africa (Int). Patients were required to meet Change From Means P Value Change From Means P Value
US Study International Study
Change From Means P Change From Means P Efficacy Scale N Baseline (95% CI) vs Placebo N Baseline (95% CI) vs Placebo
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for MDD with a 17-item Population Subset, n Placebo DVS 50 mg DVS 100 mg Placebo DVS 50 mg DVS 100 mg Analysis N Baseline (95% CI) vs Placebo N Baseline (95% CI) vs Placebo
Hamilton Rating Scale for Depression (HAM-D17) total score ≥20 at screening and baseline. Two fixed daily MADRS total score
Randomized to study 159 158 157 161 166 158
doses of desvenlafaxine (50 mg or 100 mg) or placebo were administered for 8 weeks (including a 1-week, Placebo 150 –12.3 161 –13.3
Safety population 152 151 148 161 166 158
LOCF (ANCOVA), final on-therapy DVS 50 mg 148 –15.0 2.7 (0.4, 5.0) 0.022 164 –16.4 3.1 (1.0, 5.2) 0.004
50-mg titration period for patients receiving 100 mg). The primary efficacy variable, change from baseline score
Placebo 150 –9.5 161 –10.7
Total ITT 150 150 147 161 164 158 DVS 100 mg 142 –14.3 2.0 (–0.3, 4.4) 0.095 157 –17.5 4.2 (2.1, 6.3) <0.001
on the HAM-D17, was analyzed using analysis of covariance (ANCOVA) with treatment and site as factors and DVS 50 mg 150 –11.5 1.9 (0.3, 3.5) 0.018 164 –13.2 2.5 (0.9, 4.1) 0.002
Completeda 123 115 115 147 148 128
baseline HAM-D17 score as the covariate. Clinical Global Impressions–Improvement (CGI-I) score was a DVS 100 mg 147 –11.0 1.5 (–0.1, 3.1) 0.065 158 –13.7 3.0 (1.4, 4.7) <0.001 CGI-S score
b
Discontinued, n (%)
secondary efficacy measure, which was analyzed categorically with the Cochran-Mantel-Haenszel test. For all Placebo 150 –1.2 161 –1.6
DVS 50 mg 150 –1.5 0.2 (0.0, 0.5) 0.074 164 –2.1 0.4 (0.2, 0.7) 0.003
Total 25 (16) 34 (23) 31 (21) 13 (8) 17 (10) 20 (13)
efficacy analyses, the final on-therapy evaluation was the primary end point. The primary population for efficacy
DVS 100 mg 147 –1.4 0.2 (–0.1, 0.4) 0.208 158 –2.2 0.5 (0.3, 0.8) <0.001
Observed case, week 8
analyses was the intent-to-treat (ITT) and for safety analyses was the safety population. The results from each Adverse event 4 (3) 5 (3) 11 (7) 5 (3) 8 (5) 11 (7)
Placebo 115 –10.0 138 –11.6
study are presented separately. Failed to return 6 (4) 15 (10) 11 (7) 0 0 2 (1) COVI total
DVS 50 mg 104 –12.1 2.1 (0.3, 3.9) 0.026 145 –14.7 3.1 (1.5, 4.6) <0.001
Placebo 150 –1.2 161 –1.1
DVS 100 mg 102 –11.9 1.9 (0.0, 3.7) 0.047 126 –15.2 3.6 (2.0, 5.2) <0.001
Investigator request 0 1 (1) 0 0 0 2 (1)
Results: The ITT population in the US study included 447 patients: placebo (n=150), desvenlafaxine 50 mg
DVS 50 mg 148 –1.5 0.3 (0.0, 0.6) 0.080 164 –1.7 0.6 (0.2, 0.9) 0.001
(n=150), and desvenlafaxine 100 mg (n=147). The Int study included 483 patients: placebo (n=161), Other event 3 (2) 2 (1) 3 (2) 1 (1) 0 0
DVS 100 mg 142 –1.4 0.2 (–0.2, 0.5) 0.346 157 –1.6 0.5 (0.2, 0.9) 0.004
desvenlafaxine 50 mg (n=164), and desvenlafaxine 100 mg (n=158). Mean baseline HAM-D17 scores ranged from Protocol violation 1 (1) 2 (1) 0 1 (1) 4 (2) 0
MMRM, week 8 Abbreviations: COVI, Covi Anxiety Scale; CGI-S, Clinical Global Impressions–Severity; LOCF, last observation carried forward; MADRS, Montgomery Asberg Depression Rating Scale.
23.0 to 24.4. Adjusted mean changes from baseline scores on the HAM-D17 in the US study were significantly Patient request unrelated to study 6 (4) 9 (6) 5 (3) 1 (1) 3 (2) 4 (3) Placebo 115 –9.9 138 –11.5
different for the 50-mg desvenlafaxine group versus placebo (–11.5 vs –9.5; P=0.018) but not for the 100-mg Safety
DVS 50 mg 104 –12.4 2.5 (1.1, 4.0) <0.001 145 –14.4 2.9 (1.6, 4.1) <0.001
Unsatisfactory response-efficacy 5 (3) 0 1 (1) 5 (3) 2 (1) 1 (1)
­ Rates of discontinuation due to AEs
DVS 100 mg 102 –11.9 2.03 (0.6, 3.5) 0.006 126 –14.9 3.4 (2.1, 4.7) <0.001
group (–11.0 vs –9.5; P=0.065); in the Int study changes were significantly greater for both the desvenlafaxine Abbreviations: DVS, desvenlafaxine succinate; ITT, intent-to-treat.
— US study: 7%, 3%, and 3% for the desvenlafaxine 100-mg, 50-mg, and placebo groups, respectively
50-mg (–13.2; P=0.002) and 100-mg (–13.7; P<0.001) groups compared with placebo (–10.7). On the CGI-I, a
Completers were defined as patients who had at least 53 days of exposure to the study drug. Completers were defined independently of whether patients discontinued from the
— International study: 7%, 5%, and 3% for the desvenlafaxine 100-mg, 50-mg, and placebo groups, respectively
on-therapy period of the study.
­ The most common treatment-emergent AEs are presented in Tables 5a and 5b
Abbreviations: ANCOVA, analysis of covariance; DVS, desvenlafaxine succinate; HAM-D17, 17-item Hamilton Rating Scale for Depression; LOCF, last observation carried forward;
differences between the desvenlafaxine groups and placebo were not significant in the US study; significant b
Discontinuation data are for the safety population. MMRM, mixed effects model repeated measures.
differences were observed for both desvenlafaxine groups versus placebo in the Int study (50 mg: P=0.002; 100
mg: P<0.001). In both studies, both doses of desvenlafaxine were generally well tolerated and adverse events Table 5a. Treatment-Emergent Adverse Events by Treatment Group*†, US Study
Table 2. Demographic and Baseline Characteristics, ITT Population
(AEs) were consistent with those of the SNRI class. Rates of discontinuation due to AEs in the US study were
Placebo DVS 50 mg DVS 100 mg
3%, 3%, and 7% for the placebo, desvenlafaxine 50 mg, and desvenlafaxine 100 mg groups, respectively; in US Study International Study
(n=152) (n=151) (n=148)
Adverse Event‡
the Int study were 3%, 5%, and 7%, respectively. Commonly reported AEs were: US: dry mouth (placebo: 4%; Placebo DVS 50 mg DVS 100 mg Placebo DVS 50 mg DVS 100 mg CGI-I n (%) of patients
50 mg: 11%; 100 mg: 16%), dizziness (placebo: 4%; 50 mg: 17%; 100 mg: 7%) and insomnia (placebo: 4%; 50 (n=150) (n=150) (n=147) (n=161) (n=164) (n=158)
Characteristic
Figure 2. Distribution of CGI-I Scores at the Final On-Therapy Evaluation Any adverse event 107 (70) 127 (84) 113 (76)
mg: 14%; 100 mg: 12%); Int: nausea (placebo: 11%; 50 mg: 27%; 100 mg: 30%), dry mouth (placebo: 9%; 50 42 (14) 43 (15) 43 (13) 46 (12) 44 (14) 46 (13)
Age, mean (SD), years Asthenia 5 (3) 11 (7) 10 (7)
(LOCF, ITT Population)
mg: 13%; 100 mg: 17%), and insomnia (placebo: 5%; 50 mg: 10%; 100 mg: 10%). Sex, n (%) Anorexia 7 (5) 9 (6) 15 (10)
Constipation 5 (3) 14 (9) 16 (11)
Conclusions: These results support the efficacy of desvenlafaxine 100 mg/d for improving the symptoms of Female 95 (63) 93 (62) 78 (53) 109 (68) 115 (70) 112 (71)
Dry mouth 6 (4) 16 (11) 23 (16)
MDD, and establish efficacy at the 50 mg/d dose. Male 55 (37) 57 (38) 69 (47) 52 (32) 49 (30) 46 (29) Myalgia 3 (2) 7 (5) 9 (6)
Anxiety 1 (1) 5 (3) 9 (6)
Race, n (%)
Dizziness 6 (4) 25 (17) 10 (7)
60
White 106 (71) 110 (73) 102 (69) 158 (98) 163 (99) 156 (99)
Insomnia 6 (4) 21 (14) 18 (12)
Placebo DVS 50 mg DVS 100 mg
Black 29 (19) 26 (17) 31 (21) 1 (1) 0 0 Impotence§ 0 (0) 2 (3) 4 (6)
Introduction Sweating 4 (3) 10 (7) 14 (10)
Other 15 (10) 14 (10) 14 (10) 2 (1) 1 (1) 2 (1)
50
80 (20) 86 (22)* 83 (19) 76 (18) 75 (16) 73 (18)
Weight, mean (SD), kg Abbreviation: DVS, desvenlafaxine succinate.
­ MDD is a chronic, disabling illness that is predicted to be a leading cause of disease burden worldwide in 2020, second only
Percent of patients (%)
*Events reported by at least 5% of subjects at twice the rate of placebo in either active treatment group during the double-blind period, excluding taper, safety population (all
Duration of current episode, randomized subjects who took at least one dose of double-blind test medication).
28 (46) 24 (32) 26 (45) 9 (22) 7 (12) 9 (17)
40
mean (SD), months †
Rates of nausea were: placebo 11%, desvenlafaxine 50 mg 17%, and desvenlafaxine 100 mg 16%.
to ischemic heart disease1
­ Recent World Health Organization data from 60 countries worldwide show that depression is associated with a greater
‡
Terms are derived from a Wyeth-modified COSTART dictionary.
§
Based on number of men in each treatment group (desvenlafaxine 50 mg [n=58]; desvenlafaxine 100 mg [n=69]).
Baseline HAM-D17 total score, mean (SD) 23 (3) 23 (3) 23 (3) 24 (3) 24 (2) 24 (3)
decrement in health compared with the chronic diseases angina, arthritis, asthma, or type 2 diabetes2
30
­ Desvenlafaxine, an SNRI, is the succinate salt of the major active metabolite of the antidepressant venlafaxine
Table 5b. Treatment-Emergent Adverse Events by Treatment Group,* International Study
Baseline CGI-S score, mean (SD) 4 (1) 4 (1) 4 (1) 5 (1) 5 (1) 5 (1)
Moderately ill, n (%) 104 (69) 103 (69) 93 (63) 64 (40) 70 (43) 56 (35)
(ie, O-desmethylvenlafaxine)3 Placebo DVS 50 mg DVS 100 mg
Markedly ill, n (%) 45 (30) 46 (31) 50 (34) 76 (47) 79 (48) 83 (53)
­ Results from multicenter, randomized, double-blind, placebo-controlled, parallel-group studies have demonstrated the safety 20 (n=161) (n=166) (n=158)
Adverse Event†
Severely ill, n (%) 1 (1) 1 (1) 4 (3) 21 (13) 15 (9) 19 (12)
and efficacy of desvenlafaxine using flexible doses,4,5 as well as fixed, daily doses of 100 mg, 200 mg, and 400 mg6,7 n (%) of patients
­ Data from 2 phase 3 trials are presented here:
Abbreviations: CGI-S, Clinical Global Impressions–Severity; DVS, desvenlafaxine succinate; HAM-D17, 17-item Hamilton Rating Scale for Depression; ITT, intent-to-treat.
Any adverse event 99 (62) 129 (78) 122 (77)
*P=0.046 vs placebo; this difference in baseline weight would not be expected to have any impact on the efficacy results.
10
— Objective: Compare the antidepressant efficacy, safety, and tolerability in patients receiving daily doses of desvenlafaxine at Asthenia 8 (5) 15 (9) 16 (10)
50 mg/d and 100 mg/d with placebo for the treatment of MDD Anorexia 2 (1) 9 (5) 9 (6)
Efficacy Nausea 17 (11) 44 (27) 48 (30)
— Results are reported separately for each trial
0
Primary Efficacy Measure Anxiety 5 (3) 4 (2) 11 (7)
1 1 2 2 3 3 4 4 5 5 6 6 Dizziness 6 (4) 17 (10) 11 (7)
Figure 1a. HAM-D17 Adjusted Mean Change From Baseline by Week, US Int US Int US Int US Int US Int US Int Insomnia 8 (5) 16 (10) 16 (10)
ITT Population (LOCF), US Study Somnolence 5 (3) 8 (5) 13 (8)
Methods CGI-I score*‡ Abnormal ejaculation‡ 0 0 4 (9)
DVS 50 mg DVS 100 mg
0 Placebo Abbreviation: DVS, desvenlafaxine succinate.
*Events reported by at least 5% of patients at twice the rate of placebo in either active treatment group during the double-blind period, excluding taper, safety population (all
Abbreviations: CGI-I, Clinical Global Impressions–Improvement scale; DVS, desvenlafaxine succinate; Int, international study; ITT, intent-to-treat; LOCF, last observation carried
Study Design
­ 2 identically designed, multicenter, randomized, double-blind, placebo-controlled trials were conducted: 1 in the US
randomized patients who took at least one dose of double-blind test medication).
forward; US, United States study.
-2 †
Terms are derived from a Wyeth-modified COSTART dictionary.
*CGI-I scores were categorized into 6 classes: score 1 = “very much improved”, score 2 = “much improved,” score 3 = “minimally improved,” score 4 = “no change,”
‡
Based on number of men in each treatment group (placebo [n=52]; desvenlafaxine 50 mg [n=50]; desvenlafaxine 100 mg [n=46]).
(US study) and 1 in Europe and South Africa (Int study) score 5 = “minimally worse,” score 6 = “much worse.”
Adjusted mean change
­ Screening period of 6 to 14 days ­ Desvenlafaxine treatment was associated with few clinically important changes in laboratory tests, ECG assessments, or
-4 ‡
In the international study, adjusted mean CGI-I scores were significantly different for the DVS 50 mg group (2.0, 95% confidence interval: 1.8, 2.2; P=0.003) and the DVS 100 mg
group (1.9, 95% CI: 1.7, 2.1; P<0.001), compared with the placebo group (2.5, 95% CI: 2.3, 2.7) (ANOVA analysis). The differences were not statistically significant in the US study.
­ Randomization to 8-week treatment with 1 of 2 fixed doses of desvenlafaxine (50 mg/d or 100 mg/d) or placebo. For both
from baseline
vital signs
­ Serious AEs (SAEs)
-6
desvenlafaxine arms, the starting dose was 50 mg/d; for the 100 mg/d group, patients were titrated to their maintenance
dose on study day 8 — US study: 3 patients had SAEs related to desvenlafaxine:
­ 7-day taper period following treatment (100 mg desvenlafaxine to 50 mg desvenlafaxine; other groups to placebo)
-8
H n=1 desvenlafaxine 50 mg: migraine, poststudy day 32
H n=1 desvenlafaxine 100 mg: hypotension, study day 42; discontinued due to event
-10
Patients
H n=1 desvenlafaxine 100 mg: elevated liver function test, study day 20; discontinued due to event
*
­ Healthy outpatients aged 18 years or older with a primary diagnosis of MDD (DSM-IV) for at least 30 days prior to screening
­ Screening and baseline: HAM-D17 total score ≥20, HAM-D17 item 1 (depressed mood) score ≥2, and Clinical Global
* — International study: no patients had SAEs during the on-therapy period; during the poststudy period, no patients had SAEs
-12
HAM-D17 Response and Remission
† related to study drug
­ The most common (incidence ≥5% in any treatment group, safety population) taper/poststudy-emergent AEs (TPAEs) for the
Impressions–Severity (CGI-S) scale score ≥4 (moderately ill)
Figure 3. HAM-D17 Response* and Remission† at the Final On-Therapy Evaluation
-14
Efficacy and Safety Measures desvenlafaxine 100-mg, 50-mg, and placebo groups, respectively:
0 1 2 3 4 6 8
(LOCF, ITT Population)
Efficacy — US study: dizziness (11%, 10%, 3%), nausea (10%, 6%, 3%), abnormal dreams (8%, 8%, 2%), headache (8%, 2%, 6%),
­ Primary efficacy measure: mean change from baseline to final on-therapy evaluation in total scores on the HAM-D17,
Treatment period
insomnia (7%, 2%, 4%), emotional lability (7%, 3%, 1%), hostility (6%, 6%, 1%), and diarrhea (4%, 7%, 4%)]
Abbreviations: DVS, desvenlafaxine succinate; HAM-D17, 17-item Hamilton Rating Scale for Depression; ITT, intent-to-treat; LOCF, last observation carried forward.
administered at each visit — International study: dizziness (10%, 13%, 3%), nausea (10%, 11%, 3%), headache (7%, 7%, 6%), insomnia (4%, 6%,
­ Secondary measures:
*P<0.05 DVS 50 mg vs placebo.
2%), depression (5%, 3%, 1%), and vertigo (5%, 2%, 0%)
†
P=0.006 DVS 50 mg vs placebo.
— CGI-I scale, administered at each visit after randomization Placebo DVS 50 mg DVS 100 mg
Discussion
— Response (defined as a ≥50% reduction from baseline in HAM-D17 total score)
Figure 1b. HAM-D17 Adjusted Mean Change From Baseline by Week, 70
P=0.005
— Remission (defined as a HAM-D17 total score ≤7)
­ The results demonstrate significantly greater improvements at 8 weeks for once-daily doses of desvenlafaxine 50 mg/d and
P=0.018
ITT Population (LOCF), International Study
— Montgomery Asberg Depression Rating Scale (MADRS), administered at baseline and weeks 2, 4, and 8
60
100 mg/d compared with placebo on measures of efficacy, including response and global clinical improvement
­ Desvenlafaxine 50 mg/d and 100 mg/d were also generally safe and well tolerated, with an AE profile consistent with other
— CGI-S scale, administered at each visit
DVS 50 mg DVS 100 mg
Placebo
— Covi Anxiety Scale, administered at baseline and weeks 2, 4, and 8 -1 50 SNRIs, but with a lower incidence of AEs than higher doses of desvenlafaxine
Safety P=0.003
­ At each visit: monitored AEs, vital signs, and weight
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-3
­ At screening and week 8 or early termination: physical examination, laboratory determinations, and 12-lead
Rate (%)
Adjusted mean change
40
electrocardiogram (ECG; also at baseline) -5
from baseline
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*
†
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last-observation-carried-forward (LOCF) method to account for missing data †
­ Analysis of variance was used to compare baseline characteristics of treatment groups and analysis of covariance was used
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